Mitochondrial ATP Synthase in Cardiac Biology and Disease

我们已经建立了两个独立的成年心肌细胞特异性线粒体ATP合成酶的小鼠模型 缺陷：心肌细胞特异性ATP5L基因敲除(KO)小鼠和心肌细胞特异性ATP5J KO小鼠。 对这两种模型的分析表明，线粒体ATP合成酶~90%耗尽的小鼠 在转变为致命心脏之前，出人意料地保持健康，心脏功能正常数周 衰竭伴射血分数降低(HFrEF)。父母补助金中的研究正在调查补偿性的 在线粒体ATP合酶严重耗竭的情况下维持心功能的机制 心肌细胞和最终介导向心力衰竭过渡的机制，有趣的是， 似乎不涉及心脏能量学的进一步恶化。鉴于传统观点认为 线粒体ATP合成对维持哺乳动物细胞中的能量至关重要--特别是能量-- 要求苛刻的细胞，如心肌细胞-令人惊讶的是，心肌细胞中通常水平的~10%是 足以维持小鼠的基本健康和心脏功能。我们的结果表明， 心肌细胞中的线粒体ATP合酶在静息状态下是不需要的。这种观察提出了一个问题，即 在以下条件下，心肌细胞需要多少线粒体ATP合成酶才能维持心脏功能 更耗费精力的条件，这是一个以前没有这些就无法解决的问题 老鼠模型。为了回答这个问题，有必要对小鼠施加生理压力， 增加心肌细胞的能量需求，但不同时激活病理性应激 小路。我们选择了使用异丙肾上腺素的急性β肾上腺素能刺激，并独立地使用急性 锻炼身体。附录的第二个目标是加深我们对ATP5J KO的基线描述 老鼠，这是由候选人产生的。ATP5L KO小鼠的基线特征已经是 完成。然而，在父母资助后进行的研究表明，ATP5J KO小鼠出现了 有加速的表型。因此，这些小鼠需要一个彻底的基线特征。因此， 具体目标是：1.扩展心肌细胞特异性ATP5J基因敲除小鼠的基线特征。 2.评价心肌细胞特异性ATP5L KO和ATP5J KO小鼠对生理刺激的反应 增加心肌细胞能量需求的刺激。本副刊中涉及的科学问题 与父母的资助直接相关，由此产生的信息将加强我们对 家长拨款的结果。然而，补编中的拟议工作和所需人员 它的执行与父赠与中的不同。

We have created two independent mouse models of adult cardiomyocyte-specific mitochondrial ATP synthase deficiency: cardiomyocyte-specific ATP5L knockout (KO) mice and cardiomyocyte-specific ATP5J KO mice. Analysis of both models have shown that mice with ~90% depletion of the mitochondrial ATP synthase unexpectedly remain healthy with normal cardiac function for several weeks before transitioning to lethal heart failure with reduced ejection fraction (HFrEF). Studies in the parent grant are investigating the compensatory mechanisms that maintain cardiac function in the face of severe mitochondrial ATP synthase depletion in cardiomyocytes and the mechanisms that eventually mediate the transition to heart failure which, interestingly, do not appear to involve further deterioration of cardiac energetics. Given the traditional view that the mitochondrial ATP synthesis is essential to sustain energetics in mammalian cells – especially energy- demanding cells such as cardiomyocytes – it is surprising that ~10% of its usual levels in cardiomyocytes are adequate to sustain basal mouse health and cardiac function. Our results suggest that the full complement of mitochondrial ATP synthase in cardiomyocytes is not needed at rest. This observation raises the question as to how much of the mitochondrial ATP synthase is needed in cardiomyocytes to sustain cardiac function under more energetically demanding conditions, a question that could not be previously addressed without these mouse models. To answer this question, it is necessary to impose a physiological stress on the mice that increases the energetic demands of cardiomyocytes – but without simultaneously activating pathological stress pathways. We have chosen to use acute β-adrenergic stimulation with isoproterenol and, independently, acute exercise. A second objective of the Supplement is to deepen our baseline characterization of the ATP5J KO mice, which were generated by the candidate. The baseline characterization of the ATP5L KO mice is already complete. However, studies performed after the parent grant was funded, show that the ATP5J KO mice appear to have an accelerated phenotype. Hence, these mice need a thorough baseline characterization. Thus, the specific aims are: 1. To extend the baseline characterization of the cardiomyocyte-specific ATP5J knockout mice. 2. To assess the response of cardiomyocyte-specific ATP5L KO and ATP5J KO mouse lines to physiological stimuli that increase cardiomyocyte energetic demands. The scientific questions addressed in this Supplement are directly related to those of the parent grant and the resulting information will enhance our understanding of the findings of the parent grant. However, both the proposed work in the Supplement and the personnel required to perform it are distinct from that in the parent grant.